DOCK8

This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.

Full Name

dedicator of cytokinesis 8

Function

Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PubMed:28028151, PubMed:22461490).

During immune responses, required for interstitial dendritic cell (DC) migration by locally activating CDC42 at the leading edge membrane of DC (By similarity).

Required for CD4+ T-cell migration in response to chemokine stimulation by promoting CDC42 activation at T cell leading edge membrane (PubMed:28028151).

Is involved in NK cell cytotoxicity by controlling polarization of microtubule-organizing center (MTOC), and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PubMed:25762780).

Biological Process

Cellular response to chemokine Source: UniProtKB
Dendritic cell migration Source: Ensembl
Immunological synapse formation Source: Ensembl
Memory T cell proliferation Source: MGI
Negative regulation of T cell apoptotic process Source: Ensembl
Positive regulation of establishment of T cell polarity Source: UniProtKB
Positive regulation of GTPase activity Source: UniProtKB
Positive regulation of T cell migration Source: UniProtKB
Regulation of small GTPase mediated signal transduction Source: Reactome
Small GTPase mediated signal transduction Source: InterPro

Cellular Location

Cell membrane; Lamellipodium membrane; Cytoplasm. Enriched and co-localizes with GTPase CDC42 at the immunological synapse formed during T cell/antigen presenting cell cognate interaction. Translocates from the cytoplasm to the plasma membrane in response to chemokine CXCL12/SDF-1-alpha stimulation.

Involvement in disease

Hyper-IgE recurrent infection syndrome 2, autosomal recessive (HIES2):
A rare disorder characterized by immunodeficiency, recurrent infections, eczema, increased serum IgE, eosinophilia and lack of connective tissue and skeletal involvement.
Mental retardation, autosomal dominant 2 (MRD2):
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration disrupting DOCK8 has been found in a patient with mental retardation and ectodermal dysplasia. A balanced translocation, t(X;9) (q13.1;p24). A genomic deletion of approximately 230 kb in subtelomeric 9p has been detected in a patient with mental retardation. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.

PTM

In response to chemokine CXCL12/SDF-1-alpha stimulation, phosphorylated by PRKCA/PKC-alpha which promotes DOCK8 dissociation from LRCH1.